6-thioxanthines

ABSTRACT

A 6-thioxanthine of general formula I or a pharmaceutically acceptable salt thereof ##STR1## wherein R 3  is a C 2  to C 6  alkyl, a C 3  to C 7  cycloalkyl group or a C 4  to C 8  cycloalkylalkyl group and R 8  is a C 1  to C 6  alkyl, a C 3  to C 7  cycloalkyl group or a C 4  to C 8  cycloalkylalkyl group provided that when R 3  is an ethyl, n-propyl or n-butyl group, R 8  is a C 3  to C 6  alkyl, a C 3  to C 7  cycloalkyl group or a C 4  to C 8  cycloalkylalkyl group. 
     These 3,8-disubstituted-6-thioxanthines have enhanced bronchodilator activity.

CROSS REFERENCE TO RELATED APPLICATION

This is a continuation-in-part of co-pending application Ser. No.699,254, filed Feb. 7, 1985, now U.S. Pat. No. 4,710,503.

The present invention relates to 6-thioxanthines and in particular to3,8-disubstituted-6-thioxanthines having bronchodilator activity andwhich are useful in the treatment of chronic obstructive airway disease.

Brit. J. Pharmacol., 1961, 17, 196 -207 describes3-isobutyl-6-thioxanthine. This compound (Compound No. 30 in Table 4)was tested, along with 6-thiotheophyllines(1,3-disubstituted-6-thioxanthines), 6-thiotheobromines(3,7-disubstituted-6-thioxanthines) and 6-thiocaffeines(1,3,7-trisubstituted-6-thioxanthines), for bronchodilator activity. Theauthors concluded, from these experiments, that only 6-thiotheophyllineswere of any potential therapeutic interest.

U.S. Pat. No. 4,710,503 describes certain 6-thioxanthines havingbronchodilator activity in which the 3-nitrogen is substituted by anethyl, n-propyl or n-butyl group, whilst the 8-carbon is eitherunsubstituted or substituted by a methyl or ethyl group. The preferredmaterials are said to be 3-ethyl-6-thioxanthine and3-n-propyl-6-thioxanthine.

It has now been found that 6-thioxanthines in which both the 3 and the 8positions are substituted by alkyl or cycloalkyl 9roups exhibit greaterbronchodilator activity than 6-thioxanthines in which only the 3position is substituted.

U.S. Pat. No. 4,546,182 describes 3,8-dialkylxanthines and theirbronchodilator activity. The present inventors have also found that thereplacement of the 6-oxo group, of the compounds described in U.S. Pat.No. 4,546,182, with a 6-thio group, enhances bronchodilator activity.

It is an object of the present invention to provide3,8-disubstituted-6-thioxanthines which have an enhanced bronchodilatoreffect.

Other objects and advantages of the present invention will becomeapparent from the following detailed description thereof.

According to the present invention, there is provided a 6-thioxanthineof general formula I or a pharmaceutically acceptable salt thereof##STR2## wherein R₃ is a C₂ to C₆ alkyl, a C₃ to C₇ cycloalkyl group ora C₄ to C₈ cycloalkylalkyl group, and R₈ is a C₁ to C₆ alkyl, a C₃ to C₇cycloalkyl group or a C₄ to C₈ cycloalkylalkyl group provided that whenR₃ is an ethyl, n-propyl or n-butyl group, R₈ is a C₃ to C₆ alkyl, a C₃to C₇ cycloalkyl group or a C₄ to C₈ cycloalkylalkyl group.

Preferably R₃ is a C₂ to C₅ alkyl or a C₃ to C₅ cycloalkyl group and R₈is a C₂ to C₅ alkyl or C₃ to C₅ cycloalkyl group. Preferably R₃ and R₈,when combined, contain between 5 and 8 carbon atoms. Most preferably R₃is a C₂ to C₅ alkyl group, R₈ is a C₃ to C₅ cycloalkyl group, and R₃ andR₈, when combined, contain between 5 and 8 carbon atoms. Thus R₃ may bea hexyl, methylpentyl, dimethylbutyl or ethylbutyl group, but ispreferably an ethyl, propyl, cyclopropyl, butyl, cyclobutyl, pentyl,cyclopentyl, methylbutyl, or dimethylpropyl group, whilst R₈ may bemethyl, hexyl, methylpentyl, dimethylbutyl or ethylbutyl group but ispreferably an ethyl, propyl, cyclopropyl, butyl, cyclobutyl, pentyl,cyclopentyl, methylbutyl or dimethylpropyl group.

In a particularly preferred embodiment of the present invention, R₃ isan ethyl, n-propyl or n-butyl group and R₈ is a cyclopropyl orcyclobutyl group.

The compounds of the present invention have increased bronchodilatoractivity when compared with both

(i) the equivalent xanthine, (oxygen replaces sulphur), and

(ii) the 3-substituted-6-thioxanthine obtained by replacing the 8-alkylor cycloalkyl group of a compound according to this invention by ahydrogen atom.

Thus 3-n-propyl-8-cyclobutyl-6-thioxanthine has an enhancedbronchodilator effect compared with both 3-n-propyl-8-cyclobutylxanthineand 3-n-propyl-6-thioxanthine.

Certain of these novel 6-thioxanthines may also exhibit othertherapeutic activities, for example anti-inflammatory activity.

The present invention includes pharmaceutically acceptable salts ofcompounds of general formula I with pharmaceutically acceptable bases.The term "pharmaceutically acceptable salts" means salts, the cations ofwhich are relatively innocuous to the animal organism when used intherapeutic doses so that the beneficial pharmacological properties ofthe parent compounds of general formula I are not impaired by sideeffects ascribable to the cations. Suitable salts include alkali metalsalts, e.g. sodium and potassium, ammonium salts and amine salts, suchas glycine, lysine, ethylene diamine, choline, diethanolamine,triethanolamine, octadecylamine, diethylamine, triethylamine,1-amino-2-propanol, 2-amino-2-(hydroxymethyl)- propane-1,3-diol and1-(3,4-dihydroxyphenyl)-2-isopropyl- aminoethanol.

According to a further aspect of the present invention there is provideda pharmaceutical composition for use in the treatment of chronicobstructive airway disease, comprising a 6-thioxanthine of generalformula I or a pharmaceutically acceptable salt thereof wherein R₃ andR₈ are as hereinbefore defined in conjunction with a pharmaceuticallyacceptable diluent or carrier.

In such compositions, the present thioxanthines may be the sole activeingredient. Alternatively, they may be combined with such drugsubstances as beta-agonists (e.g. salbutamol, terbutaline, rimiterol andfenoterol), calcium ion antagonists (e.g. nifedipine, verapamil anddiltiazem), and mucolytic agents (e.g. ambroxol and bromhexine).

In clinical practice, the compounds of the present invention may beadministered rectally, nasally, sublingually, by injection, byinhalation or, which is preferred, orally. The compounds may beadministered as pharmaceutical compositions in solid, semi-solid, liquidor capsule form. Usually the active ingredient will comprise between 0.1and 99% (by wt) of the pharmaceutical composition, especially between0.5 and 20% (by wt) for compositions intended for injection and between0.1 and 50% (by wt) for compositions intended for oral administration.Solid, oral dosage forms according to this invention may be prepared bycombining the active ingredient with excipients and diluents such as

(a) Binders, such as cellulose and its derivatives, starches,polyvinylpyrrolidone, natural gums, gelatin,

(b) Glidants, such as talc and fumed silica,

(c) Lubricants, such as stearate salts, PEG waxes,

(d) Disintegrants, such as starch and its derivatives, microcrystallinecellulose, croscarmellose sodium, low substituted hydroxypropylcellulose, cross linked polyvinylpyrrolidone,

(e) Diluents, such as sugars and sugar alcohols,

(f) Colorants, Flavorants and Sweeteners.

Advantageously, the solid, oral dosage form may have a protectivecoating which may, for example, serve to mask the taste of the activeingredient.

In addition to the above materials, in a further aspect of the presentinvention, the pharmaceutical composition may also contain substancessuitable for the formation of a controlled release formulation. Inparticular, the composition may contain a hydrated, water soluble,hydroxyalkyl cellulose, especially hydroxyethyl cellulose, and a higheraliphatic alcohol, especially cetostearyl alcohol, as described inBritish Pat. No. 1,405,088 (equivalent to U.S. Pat. No. 3,965,256 andU.S. Pat. No. 4,235,870), the contents of which documents are hereinincorporated by way of reference. Soft gelatin capsules consisting ofgelatin and, for example, glycerol as a plasticiser, may contain theactive ingredient in an oil, such as sesame oil, olive oil or arachisoil, or admixed with a PEG wax. Hard gelatin capsules may containgranules of the active ingredient mixed with suitable excipients anddiluents.

Liquid, oral dosage forms may be elixirs, syrups or suspensions. Suchforms may contain sweeteners, flavorants, preservatives, emulsifyingagents and dispersing agents.

Parenteral forms may be an aqueous solution or suspension of the activeingredient, optionally containing stabilising agents and/or buffersubstances.

For inhalation purposes, the active ingredient may be delivered via anaerosol or a nebuliser. The active ingredient may be present as a solid,a suspension or a solution.

The dosage of the present 6-thioxanthines that will be administered to apatient will vary within wide limits and will depend on various factorssuch as the type of patient and the disease to be treated. A suitableoral dosage may be 25 to 500 mg given 1 to 4 times a day while asuitable parenteral dose may be 10 to 250 mg also given 1 to 4 times perday.

The compounds of general formula I may be prepared by thionation of thecorresponding 6-oxo compounds. This may be performed, for example, bytreatment of the 6-oxo compounds with phosphorus pentasulphide inpyridine. This thionation is suitably carried out by treating asuspension of the 6-oxo compound in pyridine with a molar excess ofphosphorus pentasulphide (e.g. from 1.25 to 2.00 moles of P₂ S₅ per moleof 6-oxo compound).

The starting 6-oxo compounds may be prepared from 4,5-diamino-3-substituted pyrimidin-2,6-diones in the manner described in U.S. Pat.No. 4,546,182. Alternatively they may be prepared by other standardacylation procedures followed by ring closure in alkaline solution.

6-Thioxanthines according to this invention, methods of preparing suchthioxanthines and pharmaceutical compositions containing suchthioxanthines will now be described by way of example only.

EXAMPLE 1 3-(2-Methylbutyl)-8-ethyl-6-thioxanthine

3-(2-Methylbutyl)-8-ethylxanthine (13.33 gm) and phosphoruspentasulphide (14.23 gm) were refluxed in pyridine (190 ml) at a bathtemperature of 140° C. After 4.5 hr, the brown solution was cooled to10° C. and 2N sodium hydroxide {70 ml) was added. The pyridine wasremoved in vacuo from the suspension.

The residue was suspended in water (100 ml), collected and washed withcold water. The crude 6-thioxanthine was dissolved in 1N sodiumhydroxide 100 ml) and the solution was treated with 0.3 gm of charcoal,filtered, and acidified with 5N hydrochloric acid {co pH 2 -3) . Thesolid obtained was collected, washed with water and dried. The crude6-thioxanthine (11.4 gm) was then dissolved in chloroform (200 ml) andfiltered through a silica gel column. The chloroform was then evaporatedand the residue was dissolved in hot isopropanol (100 ml), treated with0.3 gm of charcoal, filtered and crystallised. 9.75 gm of crystalline6-thioxanthine (68.7% yield, mp 232°-4° C.) was obtained.

Elemental analysis for C₁₂ H₁₈ N₄ OS,

Calc: C 54.11%, H 6.81%, N 21.03%, S 12.04%

Found: C 54.0%, H 7.02%, N 21.03%, S 11.91%

EXAMPLE 2 3-Ethyl-8-n-butyl-6-thioxanthine

This compound was prepared, as described in Example 1, starting from3-ethyl-8-n-butylxanthine. Crystalline 6-thioxanthine (70% yield, mp215°-16° C.) was obtained.

Elemental analysis for C₁₁ H₁₆ N₄ OS,

Calc: C 52.37%, H 6.39%, N 22.21%, S 12.70%

Found: C 52.33%, H 6.58%, N 22.15%. S 12.73%

EXAMPLE 3 3-n-Propyl-8-n-butyl-6-thioxanthine

This compound was prepared, as described in Example 1, starting from3-n-propyl-8-n-butylxanthine. Crystalline 6-thioxanthine (83% yield, mp199°-201° C.) was obtained.

Elemental analysis for C₁₂ H₁₈ N₄ OS,

Calc: C 54.11%, H 6.81%, N 21.03%, S 12.04%

Found: C 53.98%, H 7.07%, N 20.92%, S 11.87%

EXAMPLE 4 3-n-Propyl-8-n-pentyl-6-thioxanthine

This compound was prepared, as described in Example 1, starting from3-n-propyl-8-n-pentylxanthine. Crytalline 6-thioxanthine (86% yield, mp183°-5° C.) was obtained.

Elemental analysis for C₁₃ H₂₀ N₄ OS,

Calc: C 55.70%, H 7.19%, N 19.98%, S 11.43%

Found: C 55.48%, H 7.40%, N 20.01%, S 11.21%

EXAMPLE 5 3-n-Propyl-8-cyclopropyl-6-thioxanthine

This compound was prepared, as described in Example 1, starting from3-n-propyl-8-cyclopropylxanthine. Crystalline 6-thioxanthine (76% yield,mp 261°-4° C.) was obtained.

Elemental analysis for C₁₁ H₁₄ N₄ OS,

Calc: C 52.70%, H 5.64%, N 22.39%

Found: C 52.62%, H 5.80%, N 22.39%

EXAMPLE 6 3-n-Propyl-8-cyclobutyl-6-thioxanthine

This compound was prepared, as described in Example 1, starting from3-n-propyl-8-cyclobutylxanth. Crystalline 6-thioxanthine (70% yield, mp227°-8° C.) was obtained.

Elemental analysis for C₁₂ H₁₆ N₄ OS,

Calc: C 54.55%, H 6.10%, N 21.20%, S 12.13%

Found: C 54.56%, H 6.38%, N 21.21%, S 12.30%

EXAMPLE 7 3-Isobutyl-8-butyl-6-thioxanthine

This compound was prepared, as described in Example 1, starting from3-isobutyl-8-butylxanthine. Crystalline 6-thioxanthine (81% yield, mp232°-4° C.) was obtained.

Elemental analysis for C₁₃ H₂₀ N₄ OS,

Calc: C 55.70%, H 7.19%, N 19.98%, S 11.44%

Found: C 55.56%, H 7.40%, N 19.93%, S 11.19%

EXAMPLE 8 3-n-Pentyl-8-ethyl-6-thioxanthine

This compound was prepared, as described in Example 1, starting from3-n-pentyl-8-ethylxanthine. Crystalline 6-thioxanthine (81% yield, mp193°-7° C.) was obtained.

Elemental analysis for C₁₂ H₁₈ N₄ OS,

Calc: C 54.12%, H 6.81%, N 21.04%

Found C 54.07%, H 6.88%, N 21.19%

EXAMPLE 9 3-Isopentyl-8-ethyl-6-thioxanthine

This compound was prepared, as described in Example 1, starting from3-isopentyl-8-ethylxanthine. Crystalline 6-thioxanthine (68.9% yield, mp210°-11° C.) was obtained.

Elemental analysis for C₁₂ H₁₈ N₄ OS,

Calc: C 54.11%, H 6.81%, N 21.03%, S 12.04%

Found: C 53.96%, H 7.10%, N 20.81%, S 11.81%

Choline salts of the above thioxanthines were prepared according to themethod described in K. R. H. Wooldridge etal, J.Chem. Soc., 1962, 1863.

EXAMPLE 10

Tablets having the following composition were prepared,

    ______________________________________                                        3-n-Propyl-8-n-butyl-6-thioxanthine (Example 3)                                                          50     mg                                          Hydroxypropylmethylcellulose (4000 cps)                                                                  100    mg                                          Lactose                    100    mg                                          Talc                       10     mg                                          Magnesium stearate         5      mg                                          ______________________________________                                    

EXAMPLE 11

Controlled release tablets having the following composition wereprepared,

    ______________________________________                                        3-n-Propyl-8-cyclobutyl-6-thioxanthine (Example 6)                                                       75     mg                                          Cetostearyl alcohol        30     mg                                          Hydroxyethyl cellulose     15     mg                                          Lactose                    120    mg                                          Talc                       15     mg                                          Magnesium stearate         5      mg                                          ______________________________________                                    

EXAMPLE 12

Suppositories having the following composition were prepared,

    ______________________________________                                        3-n-Propyl-8-n-butyl-6-thioxanthine (Example 3)                                                          50     mg                                          Suppository Base           1944   mg                                          Antioxidant                6      mg                                          ______________________________________                                    

EXAMPLE 13

An aerosol for inhalation was prepared containing

    ______________________________________                                        3-n-Propyl-8-n-butyl-6-thioxanthine (Example 3)                                                           2.0   g                                           Surfactant                  1.0   g                                           Propellant 11               25    g                                           Propellant 12               75    g                                           ______________________________________                                    

Pharmacological Tests Isolated Guinea Pig Trachea

The test compound was dissolved in DMSO. Guinea pig isolated trachealismuscle was mounted in a bath containing Krebs solution (pH 7.4)maintained at 37.5? C. and bubbled with carbogen (95% O₂, 5% CO₂).

Tension changes were recorded isometrically using force displacementtransducers in conjunction with potentiometric pen recorders.

The ability of the test compounds to relax airways muscle wasinvestigated by the construction of cumulative concentration effectcurves. Each concentration of the test compound was allowed toequilibrate with the tissue for 5 minutes before a concentrationincrement (ten-fold) was made.

In each tissue of 3-alkyl-8-alkyl(or cycloalkyl)-6-thioxanthine,3-alkyl-6-thioxanthine or 3-alkyl-8-alkyl(or cycloalkyl) xanthine wascompared with theophylline (as the standard). In one half of the tissuesthe theophylline was applied first, in the other half the theophyllinewas applied second. In this way the effect of order of compoundadministration on potency was minimised.

Results are given in Tables 1-9.

                  TABLE 1                                                         ______________________________________                                        Compound                In Vitro Activity                                     ______________________________________                                        Theophylline            1                                                     3-Ethyl-6-thioxanthine  3.2                                                   3-Ethyl-8-n-butylxanthine                                                                             8.2                                                   3-Ethyl-8-n-butyl-6-thioxanthine (Example 2)                                                          55.0                                                  ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Compound             In Vitro Activity                                        ______________________________________                                        Theophylline         1                                                        3-n-Propyl-6-thioxanthine                                                                          5.1                                                      3-n-Propyl-8-n-butylxanthine                                                                       8.5                                                      3-n-Propyl-8-n-butyl-6-thioxanthine                                                                43.7                                                     (Example 3)                                                                   ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        Compound             In Vitro Activity                                        ______________________________________                                        Theophylline         1                                                        3-n-Propyl-6-thioxanthine                                                                          5.1                                                      3-n-Propyl-8-n-pentyl-6-thioxanthine                                                               33.1                                                     (Example 4)                                                                   ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        Compound              In Vitro Activity                                       ______________________________________                                        Theophylline          1                                                       3-n-Propyl-6-thioxanthine                                                                           5.1                                                     3-n-Propyl-8-cyclopropylxanthine                                                                    7.1                                                     3-n-Propyl-8-cyclopropyl-6-thioxanthine                                                             433.0                                                   (Example 5)                                                                   ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                        Compound              In Vitro Activity                                       ______________________________________                                        Theophylline          1                                                       3-n-Propyl-6-thioxanthine                                                                           5.1                                                     3-n-Propyl-8-cyclobutylxanthine                                                                     8.9                                                     3-n-Propyl-8-cyclobutyl-6-thioxanthine                                                              243.6                                                   (Example 6)                                                                   ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                        Compound             In Vitro Activity                                        ______________________________________                                        Theophylline         1                                                        3-Isobutyl-6-thioxanthine                                                                          14.1                                                     3-Isobutyl-8-n-butyl-6-thioxanthine                                                                40.9                                                     (Example 7)                                                                   ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                        Compound              In Vitro Activity                                       ______________________________________                                        Theophylline          1                                                       3-(2-Methylbutyl)-8-ethylxanthine                                                                   4.4                                                     3-(2-Methylbutyl)8-ethyl-6-thioxanthine                                                             48.2                                                    (Example 1)                                                                   ______________________________________                                    

                  TABLE 8                                                         ______________________________________                                        Compound                In Vitro Activity                                     ______________________________________                                        Theophylline            1                                                     3-n-Pentyl-8-ethylxanthine                                                                            6.7                                                   3-n-Pentyl-8-ethyl-6-thioxanthine (Example 8)                                                         15.4                                                  ______________________________________                                    

                  TABLE 9                                                         ______________________________________                                        Compound                In Vitro Activity                                     ______________________________________                                        Theophylline            1                                                     3-Isopentyl-8-ethyl-6-thioxanthine (Example 9)                                                        42.2                                                  ______________________________________                                    

What is claimed:
 1. A compound selected from the group consisting of3-(2-methylbutyl)-8-ethyl-6-thioxanthine,3-ethyl-8-n-butyl-6-thioxanthine, 3-n-propyl-8-n-butyl-6-thioxanthine,3-n-propyl-8-n-pentyl-6-thioxanthine,3-n-propyl-8-cyclopropyl-6-thioxanthine,3-n-propyl-8-cyclobutyl-6-thioxanthine3-isobutyl-8-n-butyl-6-thioxanthine 3-n-pentyl-8-ethyl-6-thioxanthineand 3-isopentyl-8-ethyl-6-thioxanthine, and pharmaceutically acceptablesalts thereof.
 2. The compound of claim 1 wherein said compound is3-(2-methylbutyl)-8-ethyl-6-thioxanthine or a pharmaceuticallyacceptable salt thereof.
 3. The compound of claim 1 wherein saidcompound is 3-ethyl-8-n-butyl-6-thioxanthine or a pharmaceuticallyacceptable salt thereof.
 4. The compound of claim 1 wherein saidcompound is 3-n-propyl-8-n-butyl-6-thioxanthine or a pharmaceuticallyacceptable salts thereof.
 5. The compound of claim 1 wherein saidcompound is 3-n-propyl-8-n-pentyl-6-thioxanthine or a pharmaceuticallyacceptable salt thereof.
 6. The compound of claim 1 wherein saidcompound is 3-n-propyl-8-cyclopropyl-6-thioxanthine or apharmaceutically acceptable salt thereof.
 7. The compound of claim 1wherein said compound is 3-n-propyl-8-cyclopropyl-6-thioxanthine or apharmaceutically acceptable salt thereof.
 8. The compound of claim 1wherein said compound is 3-isobutyl-8-n-butyl-6-thioxanthine or apharmaceutically acceptable salt thereof.
 9. The compound of claim 1wherein said compound is 3-n-pentyl-8-ethyl-6-thioxanthine or apharmaceutically acceptable salt thereof.
 10. The compound of claim 1wherein said compound is 3-isopentyl-8-ethyl-6-thioxanthine or apharmaceutically acceptable salt thereof.
 11. A pharmaceuticalcomposition for use in the treatment of chronic obstruction airwaydisease comprising a 6-thioxanthine or a pharmaceutically acceptablesalt thereof according to claim 1 in conjunction with a pharmaceuticallyacceptable diluent or carrier.